title: Subanalgesic ketamine enhances morphine-induced antinociceptive activity without cortical dysfunction in rats.
abstract: OBJECTIVE
  Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, has been used for the treatment of cancer pain as an analgesic adjuvant to opioids. However, ketamine is known to produce psychotomimetic side effects including cognitive impairments under a high-dose situation, presumably as the result of cortical dysfunction. Here, we investigated whether low-dose ketamine was useful as an analgesic adjuvant to morphine for pain control, focusing on frontocortical function.
  
  
  METHODS
  To assess the analgesic effects of ketamine with or without morphine, we performed behavioral and histochemical experiments, using the hot plate test and c-Fos expression analysis in rats. The effect on cortical function was also determined by prepulse inhibition (PPI) of the acoustic startle and evoked potentials in the hippocampal CA1-medial prefrontal cortex (mPFC) synapses as measures of synaptic efficacy.
  
  
  RESULTS
  Coadministration of ketamine as a subanalgesic dose significantly enhanced intraperitoneal morphine-induced antinociceptive response, which was measured as the increased reaction latency in the hot plate test. In addition, the noxious thermal stimulus-induced c-Fos expression in the ventrolateral periaqueductal gray matter was significantly suppressed by concomitant ketamine and morphine. In contrast, the subanalgesic dose of ketamine did not impair PPI and synaptic efficacy in the mPFC.
  
  
  CONCLUSIONS
  The present results indicate that the morphine-induced analgesic effect is enhanced by a concomitant subanalgesic dose of ketamine without affecting cortical function. Our findings possibly support the clinical notion that low-dose ketamine as an analgesic adjuvant has therapeutic potential to reduce opioid dosage, thereby improving the quality of life in cancer pain patients.
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Kanazawa 1757, Ishikari-Tobetsu, 061-0293, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shikanai
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hiraide
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kamiyama
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Kiya
authors.forename: Koji
authors.initials: K
authors.lastname: Oda
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Goto
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Kei-ichi
authors.initials: K
authors.lastname: Shimamura
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Goda
authors.forename: Hiroko
authors.initials: H
authors.lastname: Togashi
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D002525:Cerebellar Cortex / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007649:Ketamine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D059408:Pain Management / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D000700:Analgesics; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D009020:Morphine